Biologists at
UCSD have discovered that the popular sedative Valium has similar
effects on the social amoeba Dictyostelium discoideum
as it does in humans. Their surprising finding that Valium,
as well as a "natural Valium" molecule found in human
brains, causes the social amoeba to enter a dormant or "sleep"
phase, may provide new insights into how cells in higher organisms,
including humans, communicate with each other.

The study, published
this week in the early on-line edition of Proceedings of the
National Academy of Sciences and to appear in the print
edition of PNAS May 24th, describes the discovery of
a short protein, or peptide, known as SDF-2, that neighboring
cells of Dictyostelium use to synchronize the formation
of spores—the dormant phase of the organism. The researchers
were surprised to find that SDF-2 is similar to a “natural
Valium” peptide—called DBI—that is found in
human brains. Both DBI and Valium cause Dictyostelium
to form spores.

“It was amusing
to discover that Valium puts Dictyostelium to sleep
and Valium puts humans to sleep,” said William Loomis,
a professor of biology at UCSD, who led the study. “But
more significantly, our findings confirm that Dictyostelium
is an excellent experimental system for studying aspects of
communication between cells that are not easily amenable to
study in complex multicellular organisms.”

Loomis and Christophe
Anjard, an assistant project scientist in Loomis’ laboratory,
and first author on the paper, also speculate that spore formation
in Dictyostelium might provide a rapid way to screen
for new drugs that mimic the anti-anxiety effects of Valium
in humans.

“Both DBI and
Valium induce spore formation in Dictyostelium, and
flumazenil, a drug that inhibits the effects of Valium in humans,
inhibits spore formation,” explained Anjard. “Using
Dictyostelium to screen for drugs that function like
Valium would be very cheap and could identify potential drugs
within hours.”

Individual cells of
Dictyostelium usually live independently, but when
food is scarce the cells form spores. During spore formation,
up to one hundred thousand cells cooperate with each other to
form a stalk that resembles a golf tee. The formation of spores
must be carefully regulated because prior to turning into spores,
cells need to climb to the top of the stalk, where they can
be more easily dispersed by the wind.

The researchers inferred
that cells at the base of the stalk cut up a longer protein
to produce the SDF-2 peptide. They said that there is much to
be learned about how DBI is made from its longer protein precursor,
and what role that longer protein may play in human cells.

“Despite the
interest in the role of DBI in the human brain, no one has really
looked to see how the DBI peptide is processed from its precursor
protein,” explained Anjard. “Also, the precursor
to SDF-2 plays a ‘housekeeping’ role in Dictyostelium
cells, shuttling fats between membranes. It would be interesting
to find out if the precursor to DBI plays a similar role in
human cells. We hope that our findings will reactivate research
in this area.”

Loomis and colleagues
are currently working to determine the crystal structure of
the receptor for the SDF-2 peptide. The researchers say that
its structure should be easier to obtain than the structure
of the receptor for DBI—also known as the GABA receptor—which
has so far been elusive. The amino acid sequence of the two
receptors is different, but because the receptor for SDF-2 responds
to DBI and Valium, its crystal structure could provide new information
about the functioning of the GABA receptor.

“The trick in
deciphering complex signals between cells is to find an experimental
system that is complex enough to have the signals that are interesting,
but simple enough to permit you to test your hypothesis,”
said Loomis. “Once you have an idea of how things work,
it is easier to go back and see if they work the same way in
a more complex system.”

“Most processes
cells use to communicate with each other have been around a
long time in evolutionary terms,” added Anjard. “For
example, we might have thought that DBI and its receptor were
unique to higher animals, but now we have discovered that this
signaling system is also being used by a single-celled organism.”